Nedd4-WW Domain-Binding Protein 5 (Ndfip1) Is Associated with Neuronal Survival after Acute Cortical Brain Injury

Abstract

Understanding the transcriptional response to neuronal injury after trauma is a necessary prelude to formulation of therapeutic strategies. We used Serial Analysis of Gene Expression (SAGE) to identify 50,000 sequence tags representing 18,000 expressed genes in the cortex 2 h after traumatic brain injury (TBI). A similar tag library was obtained from sham-operated cortex. The SAGE data were validated on biological replicates using quantitative real-time-PCR on multiple samples at 2, 6, 12, and 24 h after TBI. This analysis revealed that the vast majority of genes showed a downward trend in their pattern of expression over 24 h. This was confirmed for a subset of genes using in situ hybridization and immunocytochemistry on brain sections. Of the overexpressed genes in the trauma library, Nedd4-WW (neural precursor cell expressed, developmentally downregulated) domain-binding protein 5 (N4WBP5) (also known as Ndfip1) is strongly expressed in surviving neurons around the site of injury. Overexpression of N4WBP5 in cultured cortical neurons increased the number of surviving neurons after gene transfection and growth factor starvation compared with control transfections. These results identify N4WBP5 as a neuroprotective protein and, based on its known interaction with the ubiquitin ligase Nedd4, would suggest protein ubiquitination as a possible survival strategy in neuronal injury.

Ubiquitin ligase Nedd4 promotes α-synuclein degradation by the endosomal–lysosomal pathway

“…Previous studies also indicated that expression of Nedd4 in neurons is tightly regulated. Its expression is induced in the brain during neurogenesis (27) and after traumatic brain injury (35). Although it is possible that this build-up of Nedd4 in neurons with Lewy bodies is a consequence of neuronal damage, it seems more likely that up-regulation of Nedd4 represents a protective response that helps reduce the accumulation of this potentially toxic protein.…”

The Ubiquitin-Like SUMO System and Heart Function

“…One key example is the SUMO isopeptidase SENP3 which is one of the most prominent genes upregulated on the very first day after traumatic brain injury. 147 Under basal conditions, SENP3 is rapidly degraded via the UPS. 148 Mild oxidative stress by oxidation of cysteine 243 and 274 in SENP3 protects SENP3 from degradation, thus enhancing SENP3-mediated deSUMOylation events 149,150 ( Figure 3).…”

Nedd4 Family Interacting Protein 1 (Ndfip1) Is Required for Ubiquitination and Nuclear Trafficking of BRCA1-associated ATM Activator 1 (BRAT1) during the DNA Damage Response

“…Previous reports had shown that Ndfip1 is a cytoplasmic protein (8,17), whereas BRAT1 can shuttle between the cytoplasm and nucleus (7,18). Thus, we investigated the whereabouts of the interaction between Ndfip1 and BRAT1 using BiFC with the Venus reporter protein.…”

“…Ndfip1 was first discovered as a neuroprotective protein following traumatic brain injury (8). A number of mechanisms for Ndfip1-mediated neuroprotection have been proposed, including restricting cytoplasmic entry of toxic metals into neurons and promoting nuclear entry of PTEN, which is known for DNA repair (9,13,21).…”

“…Ndfip1 is an adaptor and activator for Nedd4 family of ubiquitin ligases, and in the adult brain, Ndfip1 is normally present in cortical neurons at low levels within vesicular membranes (12). Following injury or stress, Ndfip1 is selectively up-regulated in certain neurons, resulting in their survival (8 cumstances favoring up-regulation of Ndfip1 in some neurons but not in others are poorly understood. However, recent work from our group has defined a number of mechanisms through which Ndfip1 can combat apoptosis.…”